1. Field of the Invention
The present invention relates to a method of introducing an ultrasonic drug and an apparatus thereof, in which an ultrasonic wave is irradiated onto a subject, such as a patient, and introduces agents, such as genes or protein substances, into cells or nucleuses.
2. Description of the Related Art
In recent years, a great deal of attention has recently been given to a therapy method, such as MIT (Minimally Invasive Treatment) or a gene therapy and a regenerative medical technique, which enables a fundamental therapy in early stage. For example, diseases due to arterioscleroses or blood clots, such as an ischemic encephalopathy or a cardiac disease have a high recurrence rate. In Japan, as dietary habits change from Japanese-style food to the west, the number of hyperlipidemia patients has increased. Accordingly, a gene introduction therapy method attracts attention in which a local recurrence is suppressed or a new blood vessel is regenerated in a tissue where infarction occurs, and an ischemia symptom is improved.
A blood vessel regenerating factor accelerates regeneration of a blood vessel with respect to the limb ischemia and necrosis disease of the glycosuria symptom. The bloodstream is reduced due to the ischemia limb disease. In the West, clinical research has been performed on a gene therapy in which a blood vessel factor is introduced into a disrupted diseased part, the bloodstream regeneration is accelerated, and a therapy is performed, and the excellent result has been obtained. A blood vessel regeneration suppressing factor has an opponent function against a blood vessel regeneration factor. A blood vessel regeneration suppressing factor outputs a signal that requires blood vessel regeneration from an active tumor cell of a metabolism, and performs the proliferation. The blood vessel regeneration suppressing factor suppresses regeneration of a nutrient vessel by introducing a blood vessel regeneration factor, and suppresses the proliferation of the tumor.
As a gene therapy, a method is mainly used in which a viral vector is used from the introduction efficiency of the blood vessel regeneration factor. According to the method of using the virus vector, a target gene is introduced into retrovirus or adenovirus whose toxicity is suppressed, and the retrovirus is introduced into a gene of a target cell by the infection. Meanwhile, in recent times, in the West, the person who died due to toxicity of the virus itself has been discovered. As a result, in the inside and outside of the country, cautious theories have been presented with respect to making use of the introduction of the virus gene. In consideration of this phenomenon, another gene introducing method has been examined.
Examples of a non-virus vector method may include a chemical method in which a liposome or the like is used, and an introduction method in which a microinjection, a gene gun, an electroporation, and a laser are used. As an example of the new introduction method, an ultrasonic wave gene introduction technology to which a sonoporation phenomenon by an ultrasonic wave is applied attracts attention.
According to the method of using the ultrasonic wave gene introduction technology, a microjet is generated when an ultrasonic wave contrast medium (bubble) that is used in ultrasonic wave contrast image diagnosis collapses due to the irradiation of the ultrasonic wave, and a phenomenon (sonoporation phenomenon) is used in which a transitory hole is formed in a cell membrane. According to the method that uses the ultrasonic wave gene introduction technology, a gene or a protein is directly introduced into a cell or a nucleus through the hole generated by the sonoporation phenomenon.
Minute bubbles that are referred to as cavitations are generated by the continuous irradiation of the ultrasonic wave. Even this case, the same phenomenon as the sonoporation phenomenon is generated. According to the method that uses the ultrasonic wave gene introduction technology, generally, the bubble (contrast medium) is artificially introduced to improve the introduction efficiency. The methods that use the ultrasonic wave gene introduction technology are disclosed in JP-T-9-502191, JP-T-2001-507207, JP-T-2001-512329, JP-A-2004-261253, JP-A-6-78930, JP-A-11-226046, ‘development of ultrasonic gene introduction’ by Hiroshi FURUHATA and Yoshinobu MANOBE (BME, Japanese Society for Medical and Biological Engineering, Jul. 10, 2002, vol. 16, No. 7, pp 3 to 7), ‘therapy of ultrasonic gene introduction’ by Yoshiaki TABUCHI and Takashi KONDO (separate volume•medical advance ‘ultrasonic wave medical science front line’ published by ishiyaku Publishers, Inc., pp 203 to 208, 2004), and ‘therapy method and problem using focused ultrasonic wave’ by Katsuhiko FUJIMOTO and Takehide ASANO (separate volume•medical advance ‘ultrasonic wave medical science front line’ published by ishiyaku Publishers, Inc., pp 198 to 202, 2004).
The ultrasonic wave gene introduction technology is used together with a Levovist in which therapy approval is made as a diagnosis contrast medium or an ultrasonic wave contrast medium such as Optison in which therapy approval is not made as a diagnosis contrast medium, and enhances the drug introducing effect. The Levovist is used when movement of a tissue or the perfusion is observed on an ultrasonic wave diagnosis image. The ultrasonic wave gene introduction technology attracts attention because it enables safe introduction of the drug.
In recent times, in the ultrasonic wave diagnosis, a contrast echo method has been clinically used in which the ultrasonic wave contrast medium (microbubble) is used together. The union of the ultrasonic wave diagnosis and the ultrasonic wave therapy can be easily made. The contrast echo method is very effective as a heating therapy in which a focused ultrasonic wave is used (HIFU: High Intensity Focused Ultrasound) or a monitoring method of an ultrasonic wave therapy in an ultrasonic wave calculus fragmentation device or the like. This technology is disclosed in JP-A-6-78930, JP-A-11-226046, and ‘therapy method and problem using focused ultrasonic wave’ by Katsuhiko FUJIMOTO and Takehide ASANO (separate volume•medical advance ‘ultrasonic wave medical science front line’ published by ishiyaku Publishers, Inc., pp 198 to 202, 2004).
As a gene analysis is developed, the introducing of molecular imaging has been rapidly developed in a medical image diagnosis that has remarkably advanced on the basis of the configuration until now. The molecular imaging is largely divided into the two. One is literally one-molecular imaging that images a molecule of a nano order by using light or an X ray. The other is functional imaging that images introduction of the drug in the molecule or the metabolism, and indirectly images the behavior of the molecule. As an example of the former, a fluorescent microscope or an X ray microscope may be exemplified. An example of the latter, a nuclear medicine device (PET, SPECT) or the MRS may be exemplified.
The former is mainly used in a laboratory because of problems of a tissue invasion depth of energy or radiation exposure for imaging. In the case of the latter, nuclear species of a radiation having recognized a target molecular or a contrast medium is combined, the resolution is low but the metabolism function is enhanced, and imaging can be performed. Accordingly, the latter has been clinically used in recent times. In particular, in recent times, a new application like a PET-CT in which the PET and the X-ray CT are combined attracts much attention. In the PET, the resolution is low. In the X-ray CT, a form resolution is high. In the PET-CT, the low resolution of the PET is compensated by the high form resolution of the X-ray CT. The PET-CT displays metabolic information on a three-dimensional form image to overlap.
The molecular image by the molecular imaging images a metabolic-active tumor cell with respect to the normal tissue. In future, a gene that is introduced by a gene introduction technology using a Reporter gene moves normally into the nucleus, an expressed thing is detected by the molecule imaging technology, and the effect of the gene therapy is initially predicted. Accordingly, the molecule image can provide advantageous information together with monitoring of the therapy plan or the ultra-early diagnosis, or gene therapy.
As described above, the drug delivery method attracts attention by the combined use of the ultrasonic wave and the microbubble. However, according to the gene introduction technology using the ultrasonic wave, introduction efficiency is still lower than that in the case of using the birus vector. Since the introduction uses a sonoporation phenomenon by the microjet when the microbubble collapses, the dug can be effectively introduced into the internal organ or the tissue surface that sufficiently comes into contact with the drug. However, the introduction of the drug into the local deep part is very difficult.